4-methylthiazole derivatives, their methods of preparation and the pharmaceutical compositions in which they are present

ABSTRACT

The present invention relates to novel 4-methylthiazole derivatives, to  tr methods of preparation and to the pharmaceutical compositions in which they are present. 
     According to the invention, these derivatives have the general formula ##STR1## in which n is equal to 0 or 1 and R 1  and R 2 , which are identical or different, are selected from a hydrogen atom, a halogen, a hydroxyl group, a trifluoromethyl group, an alkyl group having from 1 to 4 carbon atoms and an alkoxy group having from 1 to 5 carbon atoms and are useful in the treatment of cardiovascular diseases associated with hyperactivity of the sympathetic nervous system.

The present invention relates to novel 4-methylthiazole derivatives,more precisely amino derivatives of 4-methyl-5-oxythiazole, to theirmethods of preparation and to pharmaceutical compositions in which theyare present.

The compounds according to the invention are 4-methylthiazolederivatives of the general formula ##STR2## which n is equal to 0 or 1and R₁ and R₂, which are identical or different, are selected from ahydrogen atom, a halogen atom, a hydroxyl group, a trifluoromethylgroup, an alkyl group having from 1 to 4 carbon atoms and an alkoxygroup having from 1 to 5 carbon atoms.

The framework of the invention also includes all the possible opticalisomers of the compounds of formula (I) and mixtures thereof.

The framework of the invention also includes the salts of theabove-mentioned compounds of formula (I).

In this formula, a halogen atom is preferably a chlorine or fluorineatom.

The alkyl and alkoxy groups can have a linear or branched chain.

An alkyl group having from 1 to 4 carbon atoms is for example a methyl,ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl group,preferably a methyl or ethyl group.

An alkoxy group having from 1 to 5 carbon atoms is for example amethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy,n-pentoxy, isopentoxy or neopentoxy group, preferably a methoxy, ethoxy,propoxy or isopropoxy group.

The general method of preparing the compounds according to the inventionof formula (I), as defined above, in which n is equal to 0 involves acondensation reaction between 5-bromo-4-methylthiazole and the sodiumsalt of a 2-(4-arylpiperazin-1-yl)ethanol, of the formula ##STR3## inwhich R₁ and R₂ are as defined above.

According to one particular characteristic, the 5-bromo-4-methylthiazoleis obtained by brominating 2-amino-4-methylthiazole under conditionswhich make it possible to obtain 2-amino-5-bromo-4-methylthiazole, anddeaminating the resulting 2-amino-5-bromo-4-methylthiazole.

2-Amino-4-methylthiazole is a known product whose method of preparationis described in the literature (Merck Index, 10th edition, no. 454).

The method of preparing the compounds according to the invention offormula (I) in which n is equal to 0 is therefore preferably carried outin three steps in accordance with the reaction scheme described below:##STR4##

The general method of preparing the compounds according to the inventionof formula (I), as defined above, in which n is equal to 1 involvesreacting 3-(4-methylthiazolyl-5-oxy)-1,2-epoxypropane with a4-arylpiperazine of the formula ##STR5## in which R₁ and R₂ are asdefined above.

According to one particular characteristic, the3-(4-methylthiazolyl-5-oxy)-1,2-epoxypropane is obtained by:

a--reaction of the sodium salt of glycerol acetonide with5-bromo-4-methylthiazole;

b--acid hydrolysis of the resulting compound under conditions which makeit possible to obtain 3-(4-methylthiazolyl-5-oxy)propane-1,2-diol; and

c--reaction of the compound obtained in step b with ethylazodicarboxylate and triphenylphosphine.

Glycerol acetonide (or 2,2-dimethyl-1,3-dioxolane-4-methanol), sold byALDRICH, is a known product whose method of preparation is described forexample in Beilstein 19, 65; Merck Index 10, 3236.

Thus the method of preparing the compounds according to the invention offormula (I) in which n is equal to 1 is therefore preferably carried outin four steps in accordance with the reaction scheme described below:##STR6##

The compounds of formula (I) according to the invention and theirpharmaceutically acceptable salts have valuable pharmacologicalproperties which make it possible to predict a therapeutic applicationof these compounds, especially in the treatment of cardiovascularmanifestations associated with hyperactivity of the sympathetic nervoussystem of the α-adrenergic type.

Thus, according to another feature, the invention also aims to covernovel pharmaceutical compositions which contain at least one compound offormula (I) or a non-toxic addition salt thereof as the activeprinciple, in association with a pharmaceutically acceptable excipient.

The pharmaceutically acceptable salts of the compounds of formula (I)are obtained in a manner known per se by bringing the products offormula (I) into contact with an appropriate amount of apharmaceutically acceptable acid such as, for example, a mineral acidlike hydrochloric acid or sulfuric acid, or an organic acid like citric,tartaric or fumaric acid.

The pharmaceutical compositions according to the invention can generallybe prepared by conventional methods and administered in an appropriatepharmaceutical form.

The compounds can be administered orally, for example, in 1 to 3 dosageunits per day, at a rate of 2 to 200 mg per dosage unit, depending onthe compound, for example in the treatment of cardiovascularmanifestations associated with hyperactivity of the sympathetic nervoussystem of the α-adrenergic type.

According to yet another feature, the invention aims to cover a methodof preparing a pharmaceutical composition, which comprises incorporatinga pharmaceutically effective amount of at least one compound of formula(I) as defined above, or a non-toxic addition salt of this compound,into a pharmaceutically acceptable excipient.

The invention finally aims to cover a method of treating cardiovascularmanifestations associated with hyperactivity of the sympathetic nervoussystem of the α-adrenergic type, which comprises administering to amammal, including man and animals, a therapeutically effective amount ofat least one compound of formula (I) as defined above, or apharmaceutically acceptable addition salt of this compound.

The invention will be illustrated with the aid of the followingnon-limiting Examples:

EXAMPLE 1 Synthesis of4-methyl-5-[2-(4-o-ethoxyphenylpiperazin-1-yl)ethoxy]thiazole (B 1258)Step 1: Synthesis of 2-amino-5-bromo-4-methylthiazole

A solution of bromine in chloroform, consisting of 66.7 ml (1.30 mol) ofBr₂ in 1000 ml of CHCl₃, is added dropwise to a solution of 120 g (1.05mol) of 2-amino-4-methylthiazole in 2300 ml of CHCl₃, with stirring.

A precipitate appears during the addition. Stirring is maintained for 48h.

The reaction medium is then filtered and the hydrobromide is washed withmethylene chloride and then with pentane.

The hydrobromide is dissolved in 2000 ml of water and then renderedbasic by the addition of 850 ml of a 10% aqueous solution of sodiumbicarbonate.

This solution is then extracted with methylene chloride. The organicphase is dried over sodium sulfate. A crystalline residue is obtainedafter removal of the solvent under vacuum.

Brown crystals: m=155 g (crude yield: 76%)

M.p._(KB) =112°-113° C.

¹ H NMR (δ ppm, DMSO) 2.05 (s, 3H, CH₃); 7.15 (s, 2H, NH₂).

Step 2: Synthesis of 4-methyl-5-bromothiazole

70.7 g (0.366 mol) of the 2-amino-5-bromo-4-methylthiazole obtained instep 1 are dissolved in a mixture of nitric acid (65%, 102 ml) andphosphoric acid (85%, 480 ml) and diazotized at between -10° C. and -5°C. with a solution of 39.4 g (0.571 mol) of sodium nitrite in 130 ml ofwater.

The reaction medium is stirred at this temperature for 30 min.Hypophosphorous acid (50%, 197 ml) is then added slowly to the reactionmedium at -10° C. After the addition, the medium is stirred at thistemperature for 3 h and the whole is then left overnight at roomtemperature.

The mixture is neutralized with a 30% aqueous solution of sodiumhydroxide (1.670 mol) and then extracted with methylene chloride. Theorganic phase is dried over sodium sulfate, the solvent is removed byevaporation under vacuum and the oil collected in this way is purifiedby passing via the hydrochloride and freeing the base again.

Yellow oil: m=31.28 g (yield 48%) n_(D) ²⁷ : 1.5735

    ______________________________________                                        C.sub.4 H.sub.4 BrNS:                                                         % Calc.    C 26.98  H 2.26   Br 44.88                                                                              N 7.87                                   % Found    C 26.80  H 2.29   Br 44.80                                                                              N 7.78                                   .sup.1 H NMR (δ ppm, DMSO)                                                                  2.35(s, 3H, CH.sub.3)                                                         9.05(s, H, Ar).                                           ______________________________________                                    

Step 3

1.4 g (0.061 mol) of sodium are added to 83.5 g (0.33 mol) of2-(4-o-ethoxyphenylpiperazin-1-yl)ethanol at 40° C. It is necessary toheat at 120° C. for 5 h in order to form the sodium salt.

9.43 g (0.053 mol) of the 4-methyl-5-bromothiazole obtained in step 2are then introduced into the reaction medium at 60°-65° C., withstirring. This temperature is maintained for 5 h and then raised to 80°C. over 1 h.

The reaction medium, with methylene chloride added, is centrifuged at3000 rpm for 15 min. After decantation and evaporation of the solventunder vacuum, the 2-(4-o-ethoxyphenylpiperazin-1-yl)ethanol is removedby fractional distillation under reduced pressure. The distillationresidue is purified by chromatography on a silica gel column (AcOEt)

The trihydrochloride is prepared in anhydrous ethyl ether by theaddition of dry gaseous HCl and then recrystallized from a mixture ofisopropanol and pentane.

M.p._(KB) =170° C. (sublimation)

C₁₈ H₂₈ Cl₃ N₃ O₂ S: 456.85

    ______________________________________                                        C.H.N    % Calc.  47.32    6.18    9.20                                                % Found  47.34    6.23    9.05                                       .sup.1 H NMR (δ ppm, DMSO-d.sub.6)                                      δ thiazole H                                                                     phenyl H O--CH.sub.2                                                                            aliph. CH.sub.2                                                                       O--CH.sub.2 --CH.sub.2                     8.85     7.00     4.60     4.05    3.10                                       (s, 1H)  (s, 4H)  (t, 2H)  (q, 2H) (t, 2H)                                    piperazine CH.sub.2                                                                          thiazole CH.sub.3                                                                          aliph. CH.sub.3                                   2.80           2.30         1.35                                              (m, 8H)        (s, 3H)      (t, 3H)                                           ______________________________________                                    

EXAMPLES 2 to 12

The following compounds were prepared using experimental proceduresanalogous to those described in Example 1, which will be readilyapparent to those skilled in the art:

--4-methyl-5-[2-(4-m-trifluoromethylphenylpiperazin-1yl)ethoxy]thiazole(B 1194),

--4-methyl-5-[2-(4-phenylpiperazin-1-yl)ethoxy]thiazole (B 1216),

--4-methyl-5-[2-(4-o-methoxyphenylpiperazin-1-yl)ethoxy]thiazole (B1223),

--4-methyl-5-[2-(4-p-fluorophenylpiperazin-1-yl)ethoxy]thiazole (B1227),

--4-methyl-5-[2-[4-(4-chloro-2-methylphenyl)piperazin-1-yl]ethoxy]thiazole(B 1259),

--4-methyl-5-[2-(4-o-fluorophenylpiperazin-1-yl)-ethoxy]thiazole (B1305),

--4-methyl-5-[2-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]ethoxy]thiazole(B 1313),

--4-methyl-5-[2-(4-m-ethoxyphenylpiperazin-1-yl)-ethoxy]thiazole (B1325),

--4-methyl-5-[2-(4-o-propoxyphenylpiperazin-1-yl)-ethoxy]thiazole (B1342),

--4-methyl-5-[2-[4-(6-chloro-2-methylphenyl)piperazin-1-yl]ethoxy]thiazole(B 1366) and

--4-methyl-5-[2-(4-o-hydroxyphenylpiperazin-1-yl)-ethoxy]thiazole (B1430).

The principal data relating to the products synthesized in Examples 1 to12 have been collated in Table 1.

                                      TABLE No. 1                                 __________________________________________________________________________     ##STR7##                                                                      Example                                                                            B                                                                                ##STR8##      Empirical formula                                                                       MW  M.p..sub.KB (°C.) Sublimation                                                 Recrystallization solvent(s)      __________________________________________________________________________    2    1194                                                                              ##STR9##     C.sub.17 H.sub.22 Cl.sub.2 F.sub.3 N.sub.3 OS                                           444.34                                                                            >140   AcOEt (washing, Δ)           3    1216                                                                              ##STR10##    C.sub.16 H.sub.24 Cl.sub.3 N.sub.3 OS                                                   412.81                                                                            >110   IPA/EtOH (1/9)                     4    1223                                                                              ##STR11##    C.sub.17 H.sub.26 Cl.sub.3 N.sub.3 O.sub.2 S                                            442.82                                                                             115   Acetone (washing)                  5    1227                                                                              ##STR12##    C.sub.16 H.sub.23 Cl.sub.3 FN.sub.3 OS                                                  430.79                                                                            >100   IPA/AcOEt (85/15)                  1    1258                                                                              ##STR13##    C.sub.18 H.sub.28 Cl.sub.3 N.sub.3 O.sub.2 S                                            456.85                                                                            >170   IPA/pentane                        6    1259                                                                              ##STR14##    C.sub.17 H.sub.24 Cl.sub.3 N.sub.3 OS                                                   424.82                                                                             >95   IPA/pentane                        7    1305                                                                              ##STR15##    C.sub.16 H.sub.22 Cl.sub.2 FN.sub.3 OS                                                  394.34                                                                            >100   IPA/pentane (95/5)                 8    1313                                                                              ##STR16##    C.sub.17 H.sub.24 Cl.sub.3 N.sub.3 OS                                                   424.82                                                                            >170   IPA/pentane                        9    1325                                                                              ##STR17##    C.sub.18 H.sub.27 Cl.sub.2 N.sub.3 O.sub.2 S                                            420.40                                                                            >120   EtOH                               10   1342                                                                              ##STR18##    C.sub.19 H.sub.28 ClN.sub.3 O.sub.2 S                                                   379.96                                                                             178   IPA/hexane (2/1)                   11   1366                                                                              ##STR19##    C.sub.17 H.sub.23 Cl.sub.2 N.sub.3 OS                                                   388.35                                                                            >120   IPA/hexane Et.sub.2 O/AcOEt        12   1430                                                                              ##STR20##    C.sub.16 H.sub.22 ClN.sub.3 O.sub.2 S                                                   355.89                                                                             180   IPA/hexane (3/1)                   __________________________________________________________________________     *Monohydrochloride                                                            **Dihydrochloride                                                             ***Trihydrochloride                                                      

EXAMPLE 13 Step 1: Synthesis of3-(4-methylthiazolyl-5-oxy)-propane-1,2-diol acetonide

6.17 g (0.268 mol) of sodium are added to 430 ml of glycerol acetonide.After 3 h 30 min at room temperature and 1 h 30 min at 50° C., 36.8 g(0.207 mol) of 5-bromo-4-methylthiazole are introduced and the reactionmedium is heated for 7 h at 110° C.

The 5-bromo-4-methylthiazole can be obtained by following theexperimental procedure described in steps 1 and 2 of Example 1.

After filtration of the medium, taking-up with methylene chloride andthen concentration under reduced pressure, the compound is purified byfractional distillation under vacuum.

B.p./0.4 mbar=95°-100° C.

n_(D) ²⁷.5 : 1.5010

¹ H NMR (δ ppm, CCl₄)

    ______________________________________                                        δ thiazole H                                                                     2 CH.sub.2 --CH                                                                           thiazole CH.sub.3                                                                        2 acetonide CH.sub.3                          8.20     3.45-4.50   2.30       1.35                                          (s, 1H)  (m, 5H)     (s, 3H)    (s, 6H)                                       ______________________________________                                    

Step 2: Synthesis of 3-(4-methylthiazolyl-5-oxy)-propane-1,2-diol

400 ml of 1N aqueous hydrochloric acid are added to a solutioncontaining 30 g (0.31 mol) of the3-(4-methylthiazolyl-5-oxy)propane-1,2-diol acetonide obtained in step 1in 1600 ml of methanol at room temperature.

The reaction medium is stirred for 15 h.

After concentration of the medium to dryness under reduced pressure, thehydrochloride is crystallized from a mixture of isopropanol and ethylether. The base is freed by the addition of a 10% solution of sodiumbicarbonate and then purified by recrystallization from a mixture ofethyl acetate and pentane (80/20) to give 19.1 g of white crystals.

M.p._(KB) =72°-73° C.

¹ H NMR (δ ppm, DMSO)

    ______________________________________                                         δ thiazole H                                                                     ##STR21##  CH.sub.2 OH .sub.--                                                                      CH.sub.2 /CH                                                                         CH.sub.3thiazole                       8.45     5          4.65       3.25-4.20                                                                            2.25                                    (s, 1H)  (d, 1H)    (t, 1H)    (m, 5H)                                                                              (s, 3H)                                 ______________________________________                                    

Step 3: Synthesis of 3-(4-methylthiazolyl-5-oxy)-1,2-epoxypropane

12.2 g (0.07 mol) of ethyl azodicarboxylate are added dropwise to asolution containing 10 g (0.053 mol) of the3-(4-methylthiazolyl-5-oxy)propane-1,2-diol obtained in step 2 and 14 g(0.053 mol) of triphenylphosphine in 200 ml of toluene at roomtemperature.

The reaction medium is heated for 10 h at 70° C.

After selective crystallization of the dicarbethoxyhydrazine and thetriphenylphosphine oxide by the addition of pentane to the reactionmedium, the filtrate is concentrated to dryness under reduced pressureand the 3-(4-methylthiazolyl-5-oxy)-1,2-epoxypropane is purified bychromatography on a silica gel column (AcOEt) to give 6.75 g of epoxidein the form of a pale yellow oil.

    ______________________________________                                        IR:  3080 cm.sup.-1,                                                                          1560 C═C,                                                                            1260 C--O,                                                                             840 C--O                                                  C═N                                                            thiazole   thiazole   thiazole epoxide                                   .sup.1 H NMR (δ ppm, DMSO)                                              δ thiazole H                                                                           CH.sub.2 /CH                                                                              thiazole CH.sub.3                                  8.4            2.6-4.5     2.2                                                (s, 1H)        (m, 5H)     (s, 3H)                                            ______________________________________                                    

Step 4: Synthesis of3-(4-o-propoxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-olmonohydrochloride (B 1395)

2.5 g (0.0113 mol) of o-propoxyphenylpiperazine are added dropwise to asolution containing 1.94 g (0.0113 mol) of the3-(4-methylthiazolyl-5-oxy)-1,2-epoxypropane obtained in step 3 in 90 mlof ethanol at room temperature.

The reaction medium is heated at 40° C. for 21 h.

The solvent is removed by distillation under reduced pressure to give anoil.

The monohydrochloride is obtained by the addition of a stoichiometricamount of an ethanolic solution of hydrochloric acid, proportionedbeforehand, to an ethanolic solution of the base, cooled in an ice bath.After stirring for 1 h and removal of the ethanol by distillation underreduced pressure, the product is crystallized from a mixture of ethylether and acetone and then recrystallized from acetone.

White crystals are obtained: 3.21 g.

M.p._(KB) =144°-145° C.

    ______________________________________                                        M.p..sub.KB = 144-145° C.                                              C.sub.20 H.sub.30 ClN.sub.3 O.sub.3 S:                                        % Calc.   C 56.13     H 7.07     N 9.82                                       % Found   C 56.50     H 7.01     N 9.80                                       .sup.1 H NMR (δ ppm, DMSO)                                              OH        thiazole H  phenyl H   CH.sub.2 --O                                 11.0      8.35        6.85       4.45                                         (m, 1H)   (s, 1H)     ("s", 4H)  (m, 2H)                                      CH.sub.2 N                                                                              thiazole CH.sub.3                                                                         propoxy CH.sub.2                                                                         propoxy CH.sub.3                             piperazine CH.sub.2                                                           CH                                                                            CH.sub.2                                                                      3.4       2.2         1.7        1                                            (m, 13H)  (s, 3H)     (m, 2H)    (t, 3H)                                      ______________________________________                                    

EXAMPLES 14 to 24

The following compounds were prepared using experimental proceduresanalogous to those described in Example 13, which will be readilyaccessible to those skilled in the art:

--3-(4-o-ethoxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol(B 1392),

--3-(4-o-hydroxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol(B 1396),

--3-[4-(4-chloro-2-methylphenyl)piperazin-1-yl]-1-(4-methylthiazolyl-5-oxy)propan-2-ol(B 1406),

--3-(4-o-isopropoxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol(B 1429),

--3-(4-o-phenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol (B1431),

--3-(4-m-trifluoromethylphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol(B 1489),

--3-(4-o-methoxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol(B 1510),

--3-(4-o-pentoxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol(B 1525),

--3-(4-m-chlorophenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol(B 1548),

--3-(4-o-isopentoxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol(B 1552) and

--3-(4-o-neopentoxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol(B 1562).

The formulae and the principal physical properties relating to theproducts synthesized in Examples 13 to 24 have been collated in Table 2.

                                      TABLE No. 2                                 __________________________________________________________________________     ##STR22##                                                                     Example                                                                            B                                                                                ##STR23##        Empirical formula                                                                       MW  M.p..sub.KB (°C.) Sublimati                                           on      Recrystallization solvent(s                                                  )                               __________________________________________________________________________    14   1392                                                                              ##STR24##       C.sub.19 H.sub.28 ClN.sub.3 O.sub.                                                      413.97                                                                            149-151                                                                              Acetone                         13   1395                                                                              ##STR25##       C.sub.20 H.sub.30 ClN.sub.3 O.sub.3 S                                                   427.99                                                                            144-145                                                                              Acetone                         15   1396                                                                              ##STR26##       C.sub.17 H.sub.24 ClN.sub.3 O.sub.3 S                                                   385.91                                                                            110    EtOH/pentane                    16   1406                                                                              ##STR27##       C.sub.18 H.sub.25 Cl.sub.2 FN.sub.3 O.sub.2                                             418.38                                                                            162-163                                                                              Ethyl acetate                   17   1429                                                                              ##STR28##       C.sub.20 H.sub.30 ClN.sub.3 O.sub.3 S                                                   427.99                                                                            174-176                                                                              Ethyl acetate/IPA               18   1431                                                                              ##STR29##       C.sub.21 H.sub.32 ClN.sub.3 O.sub.3 S                                                   442.02                                                                            170-171                                                                              Acetone/IPA                     __________________________________________________________________________     ##STR30##                                                                     Example                                                                            B                                                                                ##STR31##        Empirical formula                                                                       MW  M.p..sub.KB (°C.) Sublimati                                           on      Recrystallization solvent(s                                                  )                               __________________________________________________________________________    19   1489                                                                              ##STR32##       C.sub.18 H.sub.23 ClF.sub.3 N.sub.3 O.sub.2                                             437.91                                                                            132-134                                                                              AcOEt                           20   1510                                                                              ##STR33##       C.sub.18 H.sub.26 ClN.sub.3 O.sub.3 S                                                   399.93                                                                            120-122                                                                              AcOEt/IPA (15/1)                21   1525                                                                              ##STR34##       C.sub.22 H.sub.34 ClN.sub.3 O.sub.3 S                                                   456.04                                                                            134-136                                                                              AcOEt                           22   1548                                                                              ##STR35##       C.sub.17 H.sub.23 Cl.sub.2 N.sub.3 O.sub.2                                              404.35                                                                            124-126                                                                              AcOEt                           23   1552                                                                              ##STR36##       C.sub.22 H.sub.34 ClN.sub.3 O.sub.3 S                                                   456.04                                                                            120-122                                                                              AcOEt                           24   1562                                                                              ##STR37##       C.sub.22 H.sub.34 ClN.sub.3 O.sub.3 S                                                   456.04                                                                            166-168                                                                              AcOEt                           __________________________________________________________________________

The toxicity and the pharmacological properties of the products offormula (I) were tested and the results obtained are described below:

I. ACUTE TOXICITY IN MICE Principle of the Measurement

The products were administered orally in a single dose to male mice withan average weight of 22 g. The mortality was recorded after a 14-dayobservation period.

The results are expressed in the form of the 50% lethal dose (LD₅₀),i.e. the theoretical dose in mg.kg⁻¹, administered orally, which causesthe death of 50% of the animals.

Results

These are reported in Table 3. The majority of the molecules have anLD₅₀ of more than 1 g.kg⁻¹. These are therefore products with a lowtoxicity after a single administration.

II DETERMINATION OF THE ALPHA-BLOCKING ACTIVITY ON ISOLATED RATE VASDEFERENS Principle

Stimulation of the postsynaptic alpha-adrenergic receptors bynorepinephrine causes contraction of the isolated vas deferens.

The concentration of product in whose presence the norepinephrineconcentration must be doubled in order to obtain the same effect as inthe absence of said product is determined. The logarithm of thisconcentration, with the opposite sign, constitutes the pA₂ of theproducts.

Results

The pA₂ values reported in Table 4 show that the products behave ascompetitive norepinephrine antagonists at the alpha-adrenergicreceptors.

Their alpha-blocking activity is high since it appears for lowconcentrations of between 10⁻⁶ M and 10⁻⁸ M.

III. DETERMINATION OF THE ADRENOLYTIC ACTIVITY "IN VIVO" IN RATSPrinciple of the Measurement

The intravenous injection of norepinephrine (0.4 mg.kg⁻¹) into wake malerats causes the death of 100% of the animals. The prior administrationof a substance which has an alpha-blocking property makes it possible toreduce this toxicity.

Results

The results are expressed in the form of the 50% effective dose (ED₅₀),i.e. the dose in mg.kg⁻¹ which protects 50% of the animals (Table 5).The products B 1258, B 1242, B 1392, B 1395, B 1396, B 1429, B 1431, B1510, B 1525, B 1548 and B 1552 in particular are found to be veryactive in the whole animals, thereby confirming their actiondemonstrated in vitro.

IV. DETERMINATION OF THE INHIBITORY ACTIVITY TOWARDS HYPERTENSION INRABBITS Principle of the measurement

The blood pressure is measured by catheterization of the left carotidartery of anesthetized male rabbits. An increase in blood pressure isinduced by an intravenous injection of norepinephrine. This hypertensioncan be inhibited by the prior administration of molecules with analpha-blocking potential.

Only the compounds B 1216, B 1258, B 1305, B 1342, B 1392, B 1395 and B1431 were tested on this model.

Results

These are presented in Table 6 in the form of the 50% inhibitory dose(ID₅₀), which is defined as the dose of product which, when administeredintravenously, causes a 50% inhibition of the hypertension induced bynorepinephrine. The compound B 1395 is particularly effective with anactive dose of less than 1 mg.kg⁻¹.

V. DETERMINATION OF THE CARDIOVASCULAR ACTIVITY Principle of theMeasurement

The cardiovascular effects of three products were studied in ratsanesthetized with pentobarbital and placed under artificial respiration.The femoral blood pressure and the heart rate are recorded by means of aGOULD-BRUSH apparatus.

The products are administered intravenously in increasing doses. Threeanimals are tested per product. The dose which causes a 25% drop inaverage blood pressure (ED₂₅) was evaluated for each product andcompared with nicardipine 1 to 5 min after administration.

Results

The products have dose-dependent hypotensive effects but have little orno effect on the heart rate (Table 7). The most hypotensive in terms ofthe effective dose is B 1395 (ED₂₅ of 0.004 mg.kg⁻¹). The ED₂₅ valuesdetermined 5 min after injection make it possible to place thehypotensive potential of the products B 1395, B 1396, B 1431, B 1552 ona level with that of nicardipine.

                  TABLE No. 7                                                     ______________________________________                                        Blood pressure: Hypotension                                                                             Heart rate                                                  ED.sub.25 at 1 minute                                                                      ED.sub.25 at 5 minutes                                                                     Maximum                                     Product (mg.kg.sup.-1 I. V.)                                                                       (mg.kg.sup.-1 I. V.)                                                                       effect in %                                 ______________________________________                                        B 1258  0.8          1            -5.6                                        B 1392  0.024        0.048        -11.2                                       B 1395  0.004        0.1          -4                                          B 1396  0.008        0.06         0                                           B 1429  0.016        0.03         -5.1                                        B 1431  0.1          0.24         -12                                         B 1510  0.01         0.01         -6                                          B 1525  0.04         0.04         -8                                          B 1552  0.12         0.25         -7.9                                        NICARD- 0.0015       0.2          0                                           IPINE                                                                         ______________________________________                                    

These data make it possible to predict a good therapeutic activity ofthe compounds of formula (I) in cardiovascular manifestations associatedwith hyperactivity of the sympathetic nervous system of thealpha-adrenergic type.

                                      TABLE 3                                     __________________________________________________________________________    Acute toxicity of the various compounds in mice by oral administration        B CODE                                                                             B 1194                                                                            B 1216                                                                            B 1223                                                                            B 1227                                                                            B 1258                                                                            B 1259                                                                            B 1305                                                                            B 1313                                                                            B 1325                                                                            B 1342                                                                            B 1366                                                                            B 1392                       __________________________________________________________________________    LD.sub.50                                                                          >1000                                                                             >1000                                                                             >1000                                                                             1000                                                                              >1000                                                                              630                                                                              >1000                                                                             770 >1000                                                                             >1000                                                                               740                                                                               260                        mg.kg.sup.-1                                                                  __________________________________________________________________________    B CODE                                                                             B 1395                                                                            B 1396                                                                            B 1406                                                                            B 1429                                                                            B 1430                                                                            B 1431                                                                            B 1489                                                                            B 1510                                                                            B 1525                                                                            B 1548                                                                            B 1552                                                                            B 1562                       __________________________________________________________________________    LD.sub.50                                                                            515                                                                               315                                                                               515                                                                              428                                                                                305                                                                             1000                                                                              >1000                                                                             235 >1000                                                                              >500                                                                             >1000                                                                             >1000                        mg.kg.sup.-1                                                                  __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    Alpha-blocking activity of the products towards norepinephrine on             isolated rat vas deferens                                                     B CODE                                                                             B 1194                                                                            B 1216                                                                            B 1223                                                                            B 1227                                                                            B 1258                                                                            B 1259                                                                            B 1305                                                                            B 1313                                                                            B 1325                                                                            B 1342                                                                            B 1366                                                                            B 1392                       __________________________________________________________________________    pA.sub.2                                                                           5.59                                                                              7.05                                                                              6.57                                                                              <6  7.80                                                                              5.87                                                                              7.09                                                                              7.09                                                                              6.09                                                                              7.79                                                                              <6  7.88                         __________________________________________________________________________    B CODE                                                                             B 1395                                                                            B 1396                                                                            B 1406                                                                            B 1429                                                                            B 1430                                                                            B 1431                                                                            B 1489                                                                            B 1510                                                                            B 1525                                                                            B 1548                                                                            B 1552                                                                            B 1562                       __________________________________________________________________________    pA.sub.2                                                                           7.70                                                                              6.50                                                                              6.40                                                                              8.34                                                                              6.64                                                                              8.13                                                                              --  7.67                                                                              8.10                                                                              --  7.64                                                                              --                           __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________    Adrenolytic activity of the products on the lethal effect of                  norepinephrine in rats                                                        (ED.sub.50 = 50% effective dose)                                              B CODE                                                                             B 1194                                                                            B 1216                                                                            B 1223                                                                            B 1227                                                                            B 1258                                                                            B 1259                                                                            B 1305                                                                            B 1313                                                                            B 1325                                                                            B 1342                                                                            B 1366                                                                            B 1392                       __________________________________________________________________________    ED.sub.50                                                                          200 33  13  30  6.5 45  35  109 49   4.0                                                                              100 0.3                          mg.kg.sup.-1                                                                  __________________________________________________________________________    B CODE                                                                             B 1395                                                                            B 1396                                                                            B 1406                                                                            B 1429                                                                            B 1430                                                                            B 1431                                                                            B 1489                                                                            B 1510                                                                            B 1525                                                                            B 1548                                                                            B 1552                                                                            B 1562                       __________________________________________________________________________    ED.sub.50                                                                          0.2 0.6 8.1 0.5 8.3 0.4 59.7                                                                              0.52                                                                              1.27                                                                              15.8                                                                              1.55                                                                              --                           mg.kg.sup.-1                                                                  __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________    Inhibitory action of the compounds on the hypertension induced by             norepinephrine in anesthetized rabbits                                        (ID.sub.50 = 50% inhibitory dose)                                             B CODE                                                                             B 1194                                                                            B 1216                                                                            B 1223                                                                            B 1227                                                                            B 1258                                                                            B 1259                                                                            B 1305                                                                            B 1313                                                                            B 1325                                                                            B 1342                                                                            B 1366                                                                            B 1392                       __________________________________________________________________________    ID.sub.50                                                                          --  >3  --  --  5.6 --  3.0 --  --  7.3 --  2.6                          mg.kg.sup.-1                                                                  __________________________________________________________________________                            B CODE                                                                             B 1395                                                                            B 1396                                                                            B 1406                                                                            B 1429                                                                            B 1430                                                                            B 1431                       __________________________________________________________________________                            ID.sub.50                                                                          0.2 --  --  --  --  --                                                   mg.kg.sup.-1                                          __________________________________________________________________________

What is claimed is:
 1. 4-methylthiazole compounds of the formula##STR38## in which R₁ and R₂, which are identical or different, areselected from the group consisting of a hydrogen atom, a halogen, ahydroxyl group, a trifluoromethyl group, an alkyl group having from 1 to4 carbon atoms and an alkoxy group having from 1 to 5 carbon atoms,orpharmaceutically acceptable salts thereof.
 2. A compound of formula (I)according to claim 1, selected from the group consistingof:--3-(4-o-ethoxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol--3-(4-o-hydroxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol,--3-[4-(4-chloro-2-methylphenyl)piperazin-1-yl]-1-(4-methylthiazolyl-5-oxy)propan-2-ol,--3-(4-o-isopropoxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol,--3-(4-o-isobutoxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol,--3-(4-m-trifluoromethylphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol,--3-(4-o-methoxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol,--3-(4-o-pentoxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol,--3-(4-m-chlorophenylpiperazin-1yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol,--3-(4-o-isopentoxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-oland--3-(4-o-neopentoxyphenylpiperazin-1-yl)-1-(4-methylthiazolyl-5-oxy)propan-2-ol.3. A pharmaceutical composition which contains at least one compoundaccording to claim 1 or 2 as the active ingredient, in association witha pharmaceutically acceptable, non-toxic vehicle or carrier.